Craving has been implicated as a major contributor both to relapse and maintenance of addiction following abstinence in cocaine abusers. Although a mechanistic understanding of the biological basis of cocaine craving could identify therapeutic approaches to reduce cocaine dependence, information on the involvement of specific neurochemical systems in this phenomenon is scarce. Ongoing and previous studies in human volunteers have shown that environmental stimuli related to drug taking selectively increase cerebral glucose metabolism (Grant, 1995) and perfusion (Childress et all 1996) in cortical and limbic areas of brain and that activation in the dorsolateral prefrontal cortex and amygdala is correlated with self-reports of craving (London, 1996). We propose to elucidate the role of dopaminergic and serotonergic systems in spontaneous and cue-elicited cocaine craving, in an integrated approach utilizing positron emission tomOgraphy (PET) scanning and selective radioligands for dopamine(DA) and serotonin (5-HT) receptors and transporters. Neurochemical markers, assayed by PET, will be related to self-reports of craving in cocaine abusers, and will be compared to measures in control subjects who have no significant history of illicit dmg abuse. Our premise is that, not only is there considerable evidence in the literature for the role of dopamine and serotonin in craving, but that the activated areas, previously seen in the amygdala and dorsal lateral prefrontal cortex can be examined further by examination of these neurotransmitter systems. We hypothesize that in our experimental paradigm following withdrawal, extracellular dopamine and to a lesser extent serntonin will be decreased. It is then predicted that both intrasynaptic DA (InsDA) and intrasynaptic 5HT (Ins5HT) will increase following the pharmacologic challenge and that cue-elicited craving will correlate significantly with this increase. It is predicted that spontaneous craving however, will correlate negatively with D1 D2 and 5HT 2a receptors. Finally, it is predicted that both when cue-elicited craving is induced during PET imaging, increased InsDA and 5HT will be measurable and will correlate significantly with the craving score. Testing of these hypotheses will provide novel and fundamental answers to craving mechanisms.